While normal cells utilize a primarily oxidative metabolism to maximize energy generation from limited nutrients, oncogenic mutations drive rapid glucose consumption in cancer cells to support tumor growth and proliferation. This metabolic program is termed aerobic glycolysis and targeting this process can directly attack a fundamental property of many cancers. In particular, those cancers having the highest oncogenically- driven dependence on glycolysis will be most vulnerable to metabolic disruption. It is important, therefore, to determine the metabolic phenotype and reliance on aerobic glycolysis of cancers. My preliminary data show that T cell Acute Lymphoblastic Leukemia (T-ALL) is a cancer type that uses aerobic glycolysis and may be sensitive to metabolically targeted therapies. T-ALL occurs in both childhood and adult, with poor prognosis upon relapse in childhood or with adult onset. This leukemia is highly associated with oncogenic Notch activation and can lead to activation of the phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR pathway, which has been shown to drive aerobic glycolysis in other settings. While well characterized genetically, the metabolic program of T-ALL is poorly understood and, importantly, preliminary data from our laboratory has indicated that T-ALL cells use a metabolic program dramatically different than that of normal T cells. Specifically, our preliminary data shows that primary human T-ALL use aerobic glycolysis and overexpress the glucose transporter Glut1. Further, patient-derived T-ALL cells are highly dependent on glucose catabolism for survival. The inhibition of proteins involved in the glycolytic pathway, including Hexokinase II and pyruvate dehydrogenase kinase (PDHK), a regulator of pyruvate flux, caused rapid death in T-ALL cells but not normal T cells. Preliminary data has also shown that oncogenic Notch signaling activates the PI3K pathway, resulting in an increase in the expression of glycolytic proteins that is dependent on PI3K. I hypothesize that T-ALL utilizes a metabolic program of aerobic glycolysis that is driven by oncogenic Notch based activation of the PI3K pathway, and that oncogenic signaling enforces T-ALL reliance on aerobic glycolysis for survival and proliferation. To test this hypothesis I will: 1) Determine the metabolic program of primary human T-ALL and examine how this metabolic program is regulated; and 2) Test the reliance of T-ALL on a metabolic program of aerobic glycolysis in vivo using genetic and pharmacological approaches to delete Glut1 or inhibit PDHK. By targeting Glut1 as a powerful genetic tool to disrupt aerobic glycolysis in vivo and PDHK inhibition as a potential pharmacologic target, these studies will determine if metabolic targeting of aerobic glycolysis will be a potential new direction to treat T-ALL.